Psoriasis is a chronic complex disease, characterized by hyperproliferation of keratinocytes and increased dermal infiltration by immune cells, notably neutrophils and Th1/Th17 cells (R Heidenrich et al., Angiogenesis drives psoriasis pathogenesis, Int J Exp Pathol, 90(3):232-248, 2009) which affects about 2-4% of caucasian population (M P Schon et al., Psoriasis, New Engl J Med, 352:1899-1912, 2005). Unraveling the pathogenesis of psoriasis shows that several proangiogenic mediators are activated and highly expressed during psoriasis (R Heidenrich et al., Angiogenesis: the new potential target for the therapy of psoriasis? Drug News Perspect, 21(2):97-105, 2008). Vascular endothelial growth factor, hypoxia-inducible factor, tumor necrosis factor, interleukin-8 and angiopoietins are considered to be the main players responsible for the strong vessel formation in psoriasis. The proangiogenic milieu in the skin seems to result from a proinflammatory immune response initiated by T helper cells. Psoriasis is characterized by the formation of sharply demarked erythematous plaques with large scaling. Plaque formation occurs mainly at sites of strong mechanical stress such as the sites of stretched skin. Elbows, knees and scalp are involved in the majority of patients. Most patients with moderate to severe psoriasis require long-term systemic treatment to control their psoriasis.
In addition to markers of immune activation, markers of oxidative stress are consistently elevated in psoriasis patients and coupled with antioxidant dysfunction. These patients have increased carbonylation (oxidative stress marker) of macromolecules in skin biopsies and cultured fibroblasts, increased plasma malondialdehyde (lipid peroxidation product), increased urine 8-hydroxydeoxyguanosine (a marker of DNA oxidation) and nitrate (a product of nitric oxide), increased lipid hydroperoxides, and lower serum antioxidants (A J Gill and D L Kolson, Dimethyl fumarate modulation of immune and antioxidant responses: application to HIV therapy, Crit Rev Immunol, 33(4):307-59, 2013; references cited therein)
Psoriasis is also characterized by an impaired skin barrier (U Huffmeier, H Traupe, V Oji et al., Loss-of-function variants of the filaggrin gene are not major susceptibility factors for psoriasis vulgaris or psoriatic arthritis in German patients, J Invest Dermatol, 127:1367-1370, 2006). It has been reported that <5% of patients with psoriasis have filaggrin (FLG) mutations and 80% of psoriasis patients have FLG deficiency in their skin (U Huffmeier eta al, J Invest Dermatol, 127:1367-370, 2006). Kim et al have shown that the deficiency FLG and Loricrin (LOR) in most patients with psoriasis is due to TNF-α activation (B E Kim, M D Howell, E Guttman et al, TNF-α down regulates filaggrin and loricrin through c-Jun N-terminal kinase: Role for TNF-α antagonists to improve skin barrier, J Invest Dermatol, 13:1272-1279, 2011).
In summary, psoriasis is a chronic inflammatory skin diseases involving numerous immune axes, particularly various arms of the T-lymphocyte axis; elevated oxidative stress; impaired antioxidant responses and barrier dysfunction.
Fumaric acid occurs naturally and is an important compound biochemically since it enters into the citric acid cycle. Fumarate is a by-product at certain stages in the arginine-urea cycle and in purine biosynthesis. Since the citric acid cycle is the center for energy production, fumaric acid must be present in every cell of the body as it is a by-product of the cycle. Fumaric acid is metabolically very active. In healthy individuals, fumaric acid is formed in the skin when it is exposed to sunlight. Apparently, patients suffering from psoriasis have a biochemical defect in which they can't produce enough fumaric acid and need prolonged exposure to the sun to produce it. This is why patients frequently notice an improvement of their skin condition in the summer months and also explains, in part, the efficacy of PUVA treatment.
Fumaric acid esters (FAE) have been used for well over 25 years in the treatment of psoriasis in Europe under the trade name Fumaderm (formulation of dimethyl fumarate and ethylhydrogen fumarate) (U Mrowietz and K Asadullah, Dimethylfumarate for psoriasis: more than a dietary curiosity, Trends Mol Med, 11:43-48, 2005). 50 to about 70% psoriasis patients show clinical improvement of at least 75% after about four months treatment (D Pathirana et al., European S3-guidelines on the systemic treatment of psoriasis vulgaris, J Eur Acad Dermatol Venereol, 23 suppl 2:1-70, 2009). This treatment response is comparable to the efficacy of first generation anti-TNF-α biologics, but at a much lower cost. Long-term treatment with FAE shows favorable safety profile (J J Hoefnagel et al., Long-term safety aspects of systemic therapy with fumaric acid esters in severe psoriasis, Brit J Dermaol, 149:363-369, 2003; K Reich et al., Efficacy and safety of fumaric acid esters in the long-term treatment of psoriasis—a retrospective study (Future), J Dtch Dermatol Ges, 7:603-611, 2009).
Dimethyl fumarate (DMF) and its primary metabolite monomethyl fumarate (MMF) have been shown to increase expression of anti-inflammatory cytokines interleukin IL-10, IL-4, and IL-6 while inhibiting expression of proinflammatory cytokines IL-6, IL-1 beta, and tumor necrosis factor alpha (K Asadullah et al. Influence of monomethylfumarate on monocytic cytokine formation—Explanation for adverse and therapeutic effects in psoriasis? Arch Dermatol Res, 289:623-630, 1997; R de Jong et al., et al. Selective stimulation of T helper 2 cytokine response by the anti-psoriasis agent monomethylfumarate, Eur J Immunol, 26:2067-2074, 1996; S Schilling et al., Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration, Clin Exp Immunol, 145:101-107, 2006). MMF has also been shown to increase, on a dose-dependent basis, transglutaminase (TGase) activity, a marker of late keratinocyte differentiation, as well as keratin 10 (K10), a marker of early keratinocyte differentiation (I A Helwa et al., The mechanism of monomethyl fumarate (MMF) as an anti-psoriatic agent, J Invest Dermatol, 132:S51-S64, 2012).
A study on gene expression profiling on RNA derived from psoriatic plaque biopsies taken before and after 12 weeks of FAE treatment was recently published (A J Onderdijk et al., Regulated genes in psoriasis skin during treatment with fumaric acid esters, Brit J Dermatol, 2014). This study shows that response-to-treatment related FAE specific molecules are the transcription factors PTTG1, NR3C1, GATA3 and NG-kappaBIZ, which are important in normal cutaneous development and disease-inducing Th2 and Th17 pathways.
It is reported that after oral administration, dimethyl fumarate is rapidly cleaved into monomethyl fumarate via esterases in the small intestine (D Werdenberg et al., Presystemic metabolism and intestinal absorption of antipsoriatic fumaric acid esters, Biopharm Drug Dispos, 24:259-273, 2003). Dimethyl fumarate and the primary metabolite monomethyl fumarate have half-lives of 12 minutes and 36 hours, respectively. Peak concentrations of monomethyl fumarate are achieved within 5 to 6 hours. Although the parent compound, dimethyl fumarate, does not display protein binding, monomethyl fumarate is found to be approximately 50% bound (U Mrowietz et al., Treatment of severe psoriasis with fumaric acid esters: Scientific background and guidelines for therapeutic use. The German Fumaric Acid Ester Consensus Conference, Br J Dermatol, 141:424-429, 1999).
Metabolism of monomethyl fumarate is through the citric acid cycle leading to excretion through respiration with no known metabolism by the cytochrome P450 system (D Werdenberg et al., Presystemic metabolism and intestinal absorption of antipsoriatic fumaric acid esters, Biopharm Drug Dispos, 24:259-273, 2003; NH Litjens et al., Pharmacokinetics of oral fumarates in healthy subjects, Br J Clin Pharmacol, 58:429-432, 2004). Administration of a single fumarate tablet (containing dimethyl fumarate and calcium monoethyl fumarate) with food led to variability in serum monomethyl fumarate concentrations, suggesting that dimethyl fumarate should be taken before meals (NH Litjens et al., Pharmacokinetics of oral fumarates in healthy subjects, Br J Clin Pharmacol, 2004; 58:429-432). A more recent study focusing on the metabolites of FAE in human urine revealed what is believed to be the true mode of action of FAE and explained the discrepancy between the fact that DMF is active in-vitro and yet lacking or of low plasma level in-vivo. (M Rostami-Yazdi et al., etection of metabolites of fumaric acid esters in human urine: Implications for their mode of action, J Invest Dermatol, 129:231-24, 2009 and references cited therein). In this regard, it is known that T cells promote inflammatory events in psoriatic skin, and treatment with FAE leads to a reduction of T cells in-vivo, which is in part due to apoptosis before the clinical effect becomes evident. This effect can be explained by DMF's ability to strongly deplete intracellular glutathione which correlates well with induction of apoptosis. Another effect of FAE therapy is that peripheral blood mononuclear cells of psoriasis patients produce lower levels of pro-inflammatory Th-1 cytokines. This study reveals that a considerable part of DMF is not hydrolyzed after oral intake but enters circulation and reacts with glutathione in-vivo. In summary, the postulated mode of action of FAE is based on the ability of DMF to deplete intracellular glutathione in immune cells followed by the generation of anti-inflammatory cytokines and/or induction of apoptosis.
In-vitro studies have shown that DMF and its primary metabolite MMF induce expression of NrF2/NQO1 pathway in endothelial cells (K Benardais, R Pul, V Singh et al., Effects of fumaric acid esters on blood-brain barrier tight junction proteins, Neurosci Lett, 555:165-170, 2013). It has been found that the NrF2 pathway can be regulated by FAE in neurons and that the neuroprotective effects of fumarates are dependent on NrF2-mediated anti-oxidative pathways (R A Linker, D H Lee, S Ryan et al., Fumaric acid ester exert neuroprotective effects in neuroinflammation via activation of the NrF2 antioxidant pathway, Brain, 134:678-692, 2011). Recent human studies by Onderdijk et al. convincingly shown that the NrF2 pathway was differentially expressed in FAE responders as well as non-responders, but not in etanercept treated patients, which suggests an FAE specific effect (A J Onderdijk, D M W Balak, E M Baerveldt et al., Regulated genes in psoriasis in skin during treatment with fumaric acid esters, Brit J Dermatol, 171(4):732-741, 2014).
Furthermore, FAE specific induced pathways in the skin include activation of NrF2 and glutathione pathways (A J Onderdijk, D M W Balak, E M Baerveldt et al., Regulated genes in psoriasis in skin during treatment with fumaric acid esters, Brit J Dermatol, 171(4):732-741, 2014).
In following with and in addition to the foregoing teachings, FAEs and other fumaric acid derivatives have been proposed in the patent literature for use in treating a wide-range of diseases and conditions. A few examples are given below:                Immunological, autoimmune, and/or inflammatory processes including psoriasis                    U.S. Pat. No. 6,277,882: Joshi et. al.—Utilization of alkyl hydrogen fumarates for treating psoriasis, psoriatic arthritis, neurodermatitis and regional enteritis            US2010144651: Nilsson et. al.—Novel glucopyranose esters and glucofuranose esters of alkyl-fumarates and their pharmaceutical use                        Asthma and chronic obstructive pulmonary diseases                    US 2007/0027076: Joshi et. al.—Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma                        Cardiac insufficiency including left ventricular insufficiency, myocardial infarction and angina pectoris                    US 2007/0027076: Joshi et. al.—Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma                        Mitochondrial and neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, retinopathia pigmentosa and mitochondrial encephalomyopathy                    US 2006/0205659: Joshi et. al.—Fumaric Acid Amides            U.S. Pat. No. 6,509,376: Joshi et. al.—Utilization of dialkyfumarates            U.S. Pat. No. 6,858,750: Joshi et. al.—Use of fumaric acid derivatives for treating mitochondrial diseases            U.S. Pat. No. 7,157,423: Joshi et. al.—Fumaric acid amides                        Transplantation                    US 2006/0205659: Joshi et. al.—Fumaric Acid Amides            U.S. Pat. No. 6,359,003: Joshi et. al.—Use of fumaric acid derivatives in transplant medicine            U.S. Pat. No. 6,509,376: Joshi et. al.—Utilization of dialkyfumarates            U.S. Pat. No. 7,157,423: Joshi et. al.—Fumaric acid amides            US 2014/066505: Joshi et. al.—Utilization of Dialkylfumarates                        Autoimmune diseases including multiple sclerosis (MS)                    U.S. Pat. No. 6,509,376: Joshi et. al.—Utilization of dialkyfumarates            U.S. Pat. No. 7,157,423: Joshi et. al.—Strebel, Fumaric acid amides            US 2006/0205659: Joshi et. al.—Strebel, Fumaric Acid Amides            U.S. Pat. No. 6,436,992 and U.S. Pat. No. 7,320,999: Joshi et. al.—Use of fumaric acid derivatives            US 2008/0089896: Wang et al.—Bivalent SMAC mimetics and the uses thereof            U.S. Pat. No. 8,399,514: Lukashev et. al.—Treatment of multiple sclerosis            U.S. Pat. No. 8,669,281 B1: Zeidan et. al.—Prodrugs of fumarates and their use in treating various diseases            U.S. Pat. No. 8,759,393, U.S. Pat. No. 8,524,773, U.S. Pat. No. 7,915,310, U.S. Pat. No. 7,803,840, U.S. Pat. No. 7,619,001, and U.S. Pat. No. 7,612,110: Joshi et al.—Utilization of dialkylfumarates                        Ischemia and reperfusion injury                    US 2007/0027076: Joshi et. al.—Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma.                        
Despite their attributes, as noted above, fumarates are associated with many drawbacks. For example, therapy with fumarates products like Fumaderm frequently gives rise to flushing and/or gastro-intestinal side effects such as bloating, fullness, diarrhea, upper abdominal cramps, flatulence and nausea (Gold et al., New. Eng. J. Med., 367(12):1098-1107, 2012). Additionally, DMF and MMF are known skin sensitizers (Lammintausta et al., Contact Dermatitis, 62(2):88-96, 2010) and, therefore, present serious issues in terms of product handling. Furthermore, topical application is completely precluded and, in any event, DMF is ineffective when administered topically.
Problems are compounded by the fact that present commercially available products generally contain a combination of at least two different fumarate esters, one of which (the monomethyl ester) is present in three different forms: the calcium salt, the magnesium salt and the zinc salt). Although each individual form may have its own therapeutic profile it would be advantageous to have a much simpler and well defined product, if possible, in order to obtain a suitable therapeutic effect.
An alternative approach and the principal current trend of research for anti-psoriasis drugs is towards biologicals—a novel but costly type of therapy having many serious side effects. For example, these medications can predispose patients to infections and increase their risk of developing various malignancies. From a public health standpoint, the development of active tuberculosis in some patients with these biologicals is a matter of serious concern. Similarly, there has been found an increased risk for a variety of malignant conditions such as lymphoma, leukemia and melanomas. (Review: R K Sivamani, G Correa, Y Ono, M P Bowen, S P Raychaudhuri, E Maverakis, Biological Therapy of psoriasis, Indian J Dermatol, 55(2):161-170, 2010).
Accordingly, there is a need to develop novel therapeutically and/or prophylactically active compounds that provide an alternative to existing medicaments, especially the current commercial fumaric acid esters, and biologicals for psoriasis and other diseases. In particular, there is a need for new and/or improved oral and/or topical treatments, especially those that manifest a reduction in flushing and/or gastro-intestinal related side effects along with, most especially, particularly with respect to the latter, an increased bioavailability as well as treatments that are devoid of skin sensitization when applied topically.